Epithelial-to-mesenchymal transition and acquired resistance to sunitinib in a patient with hepatocellular carcinoma

Background & Aims: Based on the success of sorafenib, several anti-angiogenic therapies are currently evaluated in advanced hepatocellular carcinomas. Few biological data are currently available from patients that may help understanding mechanisms of acquired resistance to these drugs. Herein, we report translational data from a post-treatment surgical specimen in a patient who experienced acquired resistance to sunitinib. Methods: Clinical, radiological, and pathological data were collected before treatment, under treatment, and at the time of tumor progression. In addition, a biomolecular analysis was performed at the time of progression. Results: In this patient with non-alcoholic steatohepatitis, initial response to sunitinib was followed by tumor progression within 6 months of treatment, requesting salvage surgical resection. Surprisingly, pathological examination on post-treatment specimens revealed the presence of two juxtaposed tissue components containing either sarcomatoid-like mesenchymal cells or well- to moderately-differentiated hepatocellular carcinoma cells. Cancer cells retain a high a-fetoprotein expression in both components. However, while cells from carcinoma expressed E-cadherin but no vimentin, cancer cells from the mesenchymal component highly expressed vimentin and lost E-cadherin protein expression as measured by immunostaining. HMGA2 and Ki67 mRNA were also expressed at higher levels in mesenchymal than in carcinoma cells. Conclusion: This case report suggests the occurrence of an epithelial-to-mesenchyrnal transition in discrete areas of hepatocellular carcinomas developing resistance to sunitinib. (C) 2011 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.